Nitroxyl (HNO) has been shown to have positive cardiovascular effects in in vitro and in vivo models of failing hearts. However, at physiological pH, HNO dimerizes to hyponitrous acid, which subsequently dehydrates to nitrous oxide. Because of this metastability, HNO for therapeutic use is generated in situ from donor compounds. A variety of compounds capable of donating nitroxyl have been described and proposed for use in treating disorders known or suspected to be responsive to nitroxyl. See, e.g., U.S. Pat. Nos. 6,936,639; 7,696,373; 8,030,356; 8,268,890; 8,227,639; and 8,318,705; U.S. pre-grant publication nos. 2009/0281067; 2009/0298795; 2011/0136827; and 2011/0144067; International PCT Publication No. WO 2013/059194 and Paolocci et al., “The pharmacology of nitroxyl (HNO) and its therapeutic potential: Not just the janus face of NO,” Pharmacol. Ther. 113 (2007) 442-458. Although all of these compounds are disclosed to be capable of donating nitroxyl, they differ in various physicochemical properties, and there remains a need to identify nitroxyl donors that have physicochemical properties best suited for treating specific clinical conditions via specific routes of administration.
International PCT Publication No. WO 2013/059194 describes N-hydroxylamino-barbituric acid (HABA) type compounds that are capable of donating nitroxyl. One such compound, 5-(N-hydroxylamine)-5-ethyl-N,N-dimethylbarbituric acid (5-ethyl HABA), however, was reported to produce less than the desired amount of HNO. Further studies showed that this compound undergoes a competitive intramolecular rearrangement mechanism rather than the desired HNO producing mechanism. It was found that, by exchanging the 5-ethyl group with an O-methyloxime group, the non-HNO producing mechanism was avoided. Scheme 1 shows the major reaction pathways for the 5-ethyl HABA compound (intramolecular rearrangement pathway) and for the corresponding 5-O-methyloxime HABA compound (desired HNO producing pathway).

Accordingly, there is a need to provide new HABA type nitroxyl donating compounds that have a suitable toxicological profile and that undergo the desired HNO producing pathway under physiologically relevant conditions. Development of such compounds requires an understanding of the pharmacokinetic profile associated with nitroxyl donation and the factors influencing the toxicological profile and HNO production. Failure to understand these factors has hampered the development of nitroxyl donors for clinical use.
Citation of any reference in Section 1 of this application is not to be construed as an admission that such reference is prior art to the present application.